Abstract
Preterm birth (PTB) affects ~12% of pregnancies in the US. Despite its high mortality and morbidity, the molecular etiology underlying PTB has been unclear. Numerous studies have been devoted to identifying genetic factors in maternal and fetal genomes, but so far few genomic loci have been associated with PTB. By analyzing whole-genome sequencing data from 816 trio families, for the first time, we observed the role of fetal de novo mutations in PTB. We observed a significant increase in de novo mutation burden in PTB fetal genomes. Our genomic analyses further revealed that affected genes by PTB de novo mutations were dosage sensitive, intolerant to genomic deletions, and their mouse orthologs were likely developmentally essential. These genes were significantly involved in early fetal brain development, which was further supported by our analysis of copy number variants identified from an independent PTB cohort. Our study indicates a new mechanism in PTB occurrence independently contributed from fetal genomes, and thus opens a new avenue for future PTB research.
Highlights
Preterm birth (PTB, delivery at less than 37 weeks of gestation) affects ~10–12% of newborns in the US[1, 2], and is the leading cause for neonatal morbidity and mortality[3, 4]
We observed that these preterm-associated de novo mutations preferentially affect dosage sensitive genes that are essential in embryonic development, and these affected genes are involved in early fetal brain development
Analyzing genes affected by de novo mutations, we found that these genes were dosage sensitive, developmentally essential, and were significantly involved in early fetal brain development, suggesting a new mechanism in PTB due to fetal developmental abnormalities
Summary
Preterm birth (PTB, delivery at less than 37 weeks of gestation) affects ~10–12% of newborns in the US[1, 2], and is the leading cause for neonatal morbidity and mortality[3, 4]. In this study we directly tested an unexplored hypothesis, where fetal de novo mutations, those not inherited from parents, increase PTB risk. This hypothesis, seeks to describe a genetic mechanism for PTB solely from fetal genomes. Studying de novo mutations is fundamentally different from previous genetic studies of PTB such as genome-wide association studies, including those targeting fetal genomes. This is because the role of de novo mutations implies a novel etiologic contribution to PTB solely from fetal genomes, in contrast with the association studies for common and inherited genetic mutations from parental genomes. Like many other complex human diseases, genome-wide association studies far have not yet identified robust signals for at-risk loci for PTB, which motivated us to study PTB from other complementary etiologic perspectives
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